Our laboratory has focused on the role of papillomavirus oncoproteins in stimulating cell growth and altering cellular differentiation. We have employed two distinct cellular systems for analysis: immortalized mouse cell lines and primary human keratinocytes. Our studies with human keratinocytes and the human papillomaviruses have demonstrated the following: (1) two HPV genes are required (simultaneously) for cellular transformation and immortalization, E6 and E7; (2) HPV-18 is the most potent transforming papillomavirus and the etiology of its transforming strength lies within the LCR/E6/E7 region; (3) the in vitro transformation of human keratinocytes is a multistep process; and (4) keratinocytes transformed by HPV are resistant to growth inhibitors such as TGFbeta and the resistance to such inhibitors is the consequence of E7 gene expression (and presumably the complexation of cellular RB protein). Our studies with the BPV E5 oncoprotein in mouse cells has shown that: (1) the E5 oncoprotein forms a stable complex with a 16 kD cellular protein; (2) E5/16K complex formation appears to be essential for cellular transformation; and (3) E5/16K binding is dependent upon an intact hydrophobic domain of E5 and specifically with the presence of a glutamine residue within this domain.